The overall goal of the multidisciplinary clinical research outlined in this application is to test the hypothesis that in humans hypercholesterolemia (and other forms of hyperlipidemia) are associated with blunted skeletal muscle vasodilator responses to exercise as a result of impaired endothelial nitric oxide (NO) production. Compelling evidence to support this hypothesis comes from recent observations in ApoE knockout mice that display hypercholesterolemia, reduced endothelial function, limited exercise vasodilation, and blunted exercise tolerance. To study these issues in humans we will address the following specific aims. (1) We will determine if the blunted forearm dilator responses to endothelial agonists (i.e., acetylcholine) seen in hypercholesterolemic patients are also observed in patients with isolated hypertriglyceridemia or mixed hyperlipidemia (familial combined hyperlipidemia). (2) We will determine if a blunted dilator response to acetylcholine in hypercholesterolemic patients is associated with reduced muscle blood flow and maximal oxygen uptake (V O2max) responses to exercise. (3) We will determine if nitric oxide production (across a limb vascular bed) as assessed by conversion of arginine to citrulline is blunted during either pharmacologic stimulation of the vascular endothelium or during exercise in patients with hypercholesterolemia. (4) We will determine if treatment of hypercholesterolemia improves the vasodilator responses to acetylcholine and exercise. We will also determine if any improved vasodilator responses after treatment are associated with increased nitric oxide production and if they lead to improvements in V O2max. By addressing these specific aims we will determine if the vasodilator defects seen in patients with hypercholesterolemia during pharmacologic stimulation of vascular endothelium limit the muscle blood flow responses to exercise in humans, and whether this contributes to reduction of V O2max in these patients. We will also evaluate these issues in the context of nitric oxide production. Data from these patient- oriented studies have implications related to understanding the contribution of endothelial function in a variety of common diseases.